Millions of Americans are afflicted by neurogenerative and malignant diseases affecting the central nervous system (CNS). For many of these diseases, such as Parkinson's, Alzheimer's and high grade primary brain tumors, there is currently no curative therapy. An extensive effort has been taken to develop and test novel drugs, cell-based therapies, and gene therapy to treat these disorders. It is clear that even when effective therapeutic agents are identified, delivery into the CNS at therapeutic concentrations and sufficient distribution is a rate-limiting step to achieving clinical efficiency. The blood-brain barrier is composed of closely adhering endothelial cells, pericytes and astrocytes that tightly regulate the diffusion of molecules into the brain parenchyma. Substances with a molecular weight higher than 500 Daltons generally cannot cross the blood-brain barrier, while smaller molecules often can. Many drugs are unable to pass the barrier since the majority of them are heavier than 500 Daltons. Although efforts focused on achieving blood-brain barrier disruption and advances in endovascular delivery have shown promise, many agents such as tumor-targeted toxins, genetic vectors and chemotherapy have undesirable pharmacologic problems and systemic side effects when administered intravenously. Overcoming the drug-delivery obstacles to the CNS is a critical step in attaining better clinical outcomes.
Direct infusion of drugs into the brain parenchyma using convection-enhanced delivery (CED) results in the treatment of large areas of brain tissue and concentrates the infusate in situ, thereby circumventing the delivery obstacles posed by the blood-brain barrier and dilution of infusate in the blood. CED is a technique that relies on bulk flow to establish a pressure gradient over time, resulting in continuous convective flow and widespread distribution of the infusate to the affected areas of the brain. The extent of drug distribution using CED depends on many factors including: (1) interstitial pressure; (2) type of tissue infused (tumor, grey matter, white matter); (3) molecular weight of infusate; (4) volume and flow rate during administration; and (5) diameter/type of drug delivery catheter.
One limitation related to conventional CED treatment involves the backflow of infusate along the catheter body at increased infusion rates, which can be exasperated following introduction using a removable introducer. Backflow generally occurs as a result of excessive fluid infusion pressure at higher flow rates that preferentially drives the fluid up the catheter shaft as the path of least resistance. When using an introducer to place the catheter in tissue and due to the outer diameter of the introducer being necessarily greater than the outer diameter of the drug delivery catheter, this creates a post-introducer tissue compression, thereby creating a preferential gap and lower flow resistance along the catheter body, resulting in increased backflow or reflux of infusate during treatment at high injection flow rates as compared to catheters placed without introducers.
Another limitation relates to uneven distribution of infusate in brain tumor tissue as opposed to normal brain tissue. While the interstitial pressure of normal brain tissue is relatively low, (1-2 mm Hg), the interstitial pressure in brain tumor tissue can be over twenty-five times greater, which may account for uneven distribution and leakage of infusate into the subarachnoid space. This phenomenon is not surprising considering that most catheters used for CED have a single lumen from which infusate is delivered and the infusate may follow the path of lowest interstitial pressure. Additionally, it has been documented that multiport catheters may only infuse through one or two ports (that have least resistance to outflow) when eight are present, rendering the majority of ports useless for drug delivery. As an example, gliomas are composed of necrotic areas and regions of infiltrating tumor cells into the normal brain tissue, therefore the interstitial pressure varies greatly, creating counterproductive pressure gradients in peritumoral tissue. Use of CED in normal brain tissue with low flow rates (i.e., 0.1 μl/min) results in relatively homogenous distribution, but higher flow rates (i.e., 5 μl/min) results in reflux of the infusate back along the catheter track and away from the target tissue. Attempting to infuse large volumes, over a short time period, results in a deforming force on tissue, eventually narrowing the interstitial space and promoting a shear plane and tissue tearing. Therefore, a long administration time is required to administer even 1 ml of infusate because higher flow rates negate the desired distribution of drug using CED. What is clearly needed, therefore, and would be beneficial to treating brain tumor patients by CED, are new types of catheters and methods capable of increasing flow rate and decreasing total infusion time thereby shortening clinical procedures, while also minimizing reflux and allowing for more homogenous delivery of infusate.
Hollow fiber membranes are made from porous polymers and have been incorporated into catheters that improve the distribution of drugs administered directly into the central nervous system and other tissues. It has been found that using a porous polymer hollow fiber significantly increases the surface area of brain tissue that the drug or therapeutic fluid is infused into. Hollow fiber membranes create a very low pressure for fluid injection such that the risk for backflow is reduced while creating overall higher flow rates with the large surface area of the hollow fiber membrane. Dye was infused into a mouse brain by convection-enhanced delivery using a 28 gauge needle compared to a hollow fiber having a 3 mm length. Hollow fiber mediated infusion increased the volume of brain tissue labeled with dye by a factor of 2.7 times compared to using a needle. In order to determine if hollow fiber use could increase the distribution of gene therapy vectors, a recombinant adenovirus expressing the firefly luciferase reporter was injected into the mouse striatum. Gene expression was monitored using in vivo luminescent imaging. In vivo imaging revealed that hollow fiber mediated infusion of adenovirus resulted in gene expression that was an order of magnitude greater than when a conventional needle was used for delivery. To assess distribution of gene transfer, an adenovirus expression green fluorescent protein was injected into the striatum using a hollow fiber and a conventional needle. The hollow fiber greatly increased the area of brain transduced with adenovirus relative to a needle, transducing a significant portion of the injected hemisphere as determined by histological analysis.
On a separate subject, Applicant has previously disclosed and claimed various applications for the use of hollow fibers in various medical applications, including microdialysis, ultrafiltration and so forth. See, for instance, PCT application serial numbers PCT/US98/16416, filed 7 Aug. 1998, PCT/US03/08921, filed 21 Mar. 2003 and corresponding U.S. applications, all of which are incorporated herein by reference.